An immunotolerant HER-2/neu transgenic mouse model of metastatic breast cancer
Hong Song1, Karineh Shahverdi, David L Huso
1Division of Nuclear Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21231, USA.
Purpose:
Animal models of breast cancer metastases that recapitulate the pattern of metastatic progression seen in patients are lacking; metastatic breast cancer models do not currently exist for evaluation of immune-mediated therapies. We have developed and characterized a preclinical model for the evaluation of immune-mediated metastatic breast cancer therapies.
Experimental Design:
The NT2.5 mammary tumor cell line was injected into the left cardiac ventricle of immunotolerant transgenic neu-N mice and athymic nu/nu mice. Metastatic progression was monitored by bioluminescent, small-animal magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography/computed tomography imaging, and also by histopathology. Antigen expression in normal organs and tumor metastases was evaluated by Western blot analysis and flow cytometry.
Results:
Left cardiac ventricle injection of NT2.5 cells yielded widespread metastases in bones, liver, and spleen. Three to four weeks after injection, mice exhibited hind limb paralysis and occasional abdominal enlargement. Bioluminescence imaging of metastatic progression was successful in nude mice but the bioluminescent cells were rejected in immunocompetent mice. Other imaging modalities allowed successful imaging of nonbioluminescent cells. Small-animal positron emission tomography imaging allowed visualization of disease, in vivo, in the bones and liver. Magnetic resonance imaging revealed initial dissemination of the tumor cells to the bone marrow. Small-animal single-photon emission computed tomography/computed tomography imaging identified metastatic bone lesions targeted by a radiolabeled antibody.
Conclusion:
The model closely recapitulates the pattern of metastatic spread in breast cancer. This immunotolerant metastatic model is a novel addition to existing breast cancer models and coupling the model with in vivo imaging greatly facilitates the evaluation of targeted immunotherapies of metastasis.
Insights
Researchers developed a new preclinical model for breast cancer metastasis, enabling the evaluation of immunotherapies. This model successfully mimics metastatic spread and aids in assessing targeted treatments for metastatic breast cancer.
Area of Science:
- Oncology
- Immunology
- Preclinical Research
Background:
- Existing animal models do not accurately replicate human breast cancer metastasis patterns.
- There is a lack of suitable models for evaluating immune-mediated therapies in metastatic breast cancer.
Purpose of the Study:
- To develop and characterize a novel preclinical model for evaluating immune-mediated therapies targeting breast cancer metastasis.
- To create a model that recapitulates the metastatic progression observed in patients.
Main Methods:
- The NT2.5 mammary tumor cell line was injected into the cardiac ventricle of immunotolerant and athymic mice.
- Metastatic progression was monitored using various imaging techniques, including bioluminescence, PET, and MRI.
- Antigen expression was assessed via Western blot and flow cytometry.
Main Results:
- Widespread metastases to bones, liver, and spleen were observed.
- Bioluminescence imaging was effective in nude mice but not immunocompetent mice; other modalities successfully imaged nonbioluminescent cells.
- PET and MRI visualized disease in bones and liver, while SPECT/CT identified bone lesions.
Conclusions:
- The developed model closely mimics human breast cancer metastatic spread.
- This immunotolerant model, combined with advanced imaging, is valuable for evaluating immunotherapies for metastasis.
- It represents a significant advancement for breast cancer research and therapeutic development.
